Dysfunction of glycogen synthase-3 (GSK-3 or ser9-pGSK3?) has been linked to the etiology of central nervous system diseases such as bipolar disorder, schizophrenia, Alzheimer's disease and Parkinson's disease and is a target for therapeutic development. The goal of this proposal is to develop a GSK-3 positron emission tomography (PET) imaging agent for in vivo evaluation in rodent and monkey brains in order to facilitate its successful translation into clinical studies of diagnosis, treatment monitoring and drug development. A radiotracer for PET imaging of the GSK-3 kinase could be used both for study of its role in psychiatric disorders and accelerate target occupancy studies as part of the development of small molecule inhibitors of GSK-3 as therapeutic agents. At present there is no validated PET tracer available for the in vivo monitoring of GSK-3 in brain. Hence we propose to develop specific radiotracers for PET imaging GSK-3 and have selected 1-(7-methoxyquinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (A1070722) as the first candidate for testing from a set of four structurally diverse GSK-3 ligands (Figure 2). A1070722 is a high affinity (Ki = 0.6 nM) and selective ligand for GSK-3 with favorable logP (3.2) for blood brain barrier (BBB) penetration. A1070722 is known to enter brain and reduces phosphorylation of microtubule-associated protein Tau. We synthesized [11C]A1070722 ([11C]1, > 40% yield; > 98% purity) and in this application we propose to evaluate the in vivo distribution of [11C]A1070722 in brain by PET imaging. Parallel to the PET evaluation of [11C]1 in rats, two highly selective dihydro-3H-pyrazol-3-on based GSK-3 ligands 2 & 3 and a high affinity oxadiazabenzonitrile ligand (4) will be synthesized as back-up candidate ligands. The back-up ligands will be further assayed to determine their selectivity to GSK-3. Based on specified criteria including affinity for GSK-3 relative to other targets, the candidates will be radiolabeled and their in vivo ability to bind GSK-3 will be determined in rats in vivo with microPET imaging. These studies will prove the BBB permeability, brain distribution, in vivo stability, specific binding and tracer clearance in rats. The optimal candidate will then be advanced to PET studies in monkeys for determination of more detailed brain distribution, specific binding relative to nonspecific binding and tracer kinetic modeling. Test-retest data from the monkey study will be used to choose an optimal method for determining the outcome measure. Successful completion of the proposed studies would lead to the identification of a valuable tool for in vivo quantification of GSK-3 using PET imaging in the normal brain and pathogenesis of several major brain disorders and development of new therapeutic treatments targeting GSK-3.